{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T16:43:01Z","timestamp":1776357781901,"version":"3.51.2"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1232"],"award-info":[{"award-number":["W1232"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The serotonin transporter (SERT) belongs to the family of neurotransmitter sodium symporters (NSS), together with other neurotransmitter transporters for norepinephrine, dopamine, glycine, and GABA. The main physiological role of SERT is the retrieval of previously released serotonin from the synaptic cleft. Thereby, SERT plays an important role in regulating the extracellular serotonin concentration and maintaining serotonergic neurotransmission. This process can be influenced by molecules acting as serotonin uptake inhibitors, like paroxetine. Here, we report the development of a novel photoswitchable paroxetine derivative and its pharmacological interaction profile with SERT as a tool compound for the light\u2010induced control of SERT. Based on the azo\u2010extension strategy, the photoswitchable moiety was formed at the former position of the fluoro substituent in paroxetine. The resulting azo\u2010paroxetine (<jats:bold>9<\/jats:bold>) was easily and reversibly switched between active (<jats:italic>Z<\/jats:italic>) and inactive (<jats:italic>E<\/jats:italic>) configurations and remained stable between these configurations: serotonin uptake was inhibited more than 12 times more potently by the active (<jats:italic>Z<\/jats:italic>)\u2010configuration having a sub \u03bcM IC<jats:sub>50<\/jats:sub> value. This was supported by electrophysiological patch\u2010clamp recordings in the whole\u2010cell configuration and docking studies. No significant toxic impact of azo\u2010paroxetine (<jats:bold>9<\/jats:bold>) and no off\u2010target activity at the norepinephrine transporter (NET), human GABA transporter subtypes 1 and 3, and rat GAT1 were observed. Our results demonstrate that the activity of SERT can be reversibly manipulated by the optopharmacological agent azo\u2010paroxetine (<jats:bold>9<\/jats:bold>). This compound can thus be applied as a tool for the selective manipulation of SERT in central or peripheral investigations, further benefiting from its low probability for compound\u2010related off\u2010target effects.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70068-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.70068","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T09:05:08Z","timestamp":1745485508000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Careful Examination of a Novel Azobenzene Paroxetine Derivative and Its Interactions With Biogenic Amine Transporters"],"prefix":"10.1111","volume":"169","author":[{"given":"Dominik","family":"Dreier","sequence":"first","affiliation":[{"name":"Institute of Applied Synthetic Chemistry TU Wien  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver John V.","family":"Belleza","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Schl\u00f6gl","sequence":"additional","affiliation":[{"name":"Institute of Applied Synthetic Chemistry TU Wien  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Kickinger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry University of Vienna  Vienna 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